Hydroxamic and carboxylic acid derivatives

ABSTRACT

A phacologically actve compound of forula (1)  
                 
 
     wherein  
     R 1  is OH or NHOH  
     R 2  is H, alkyl, alkenyl, aryl, arylakyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloakylalkyl, heterocyclo, or heterocycloalkyl (any of which may be optionally substituted with one or more substituents selected from R 6 , W and WR 6 ); and  
     R 3  is H or alkyl;  
     or R 2 , R 3  and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substituents selected fom R 6 , W and WR 6 );  
     R 4  is alkyl, cycloalkyl, OR 9 , CO 2 R 14 , COR 10 , S(O) q R 10  where q is 0.1 or 2, CONR 7 R 8 , CN or S(O) q NR 7 R 4 ; substituents may be attached to th same carbon atom to from C(R 4 ) 2 , where each R 4  may be the same or dfferent, and C(R 4 ) 2  may represent C═O;  
     R 5  is aklyl, cycloalkyl, aryl, heteroaryl, hetrocyclo, CF 3 , OR 9 , COR 10 , S(O) 9 R 10 , CO 2 R 14 , CONR 7 R 8 , S(O)NR 7 R 8 . halogen, NR 10 R 11  or CN, or two adjacent R 5  substituents may be combined to form a heterocyclic ring,  
     R 6  is OR 9 , COR 10 , CO 2 R 15 , CONR 7 R 8 , NR 10 R 11 , S(O) 9 R 10 , S(O) 9 NR 7 R 8 , ═O, ═NOR 10 , succinimido or the group  
                 
 
     R 7  and R 8 , which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl, or cycloalkylalkyl, or R 7  and R 8  and the nitrogento which they are attached together represent a heterocyclic ring;  
     R 9  is alkyl, CF 3 , CHF 2 , CH 2 F, cycloalkyl, aryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl,  
     R 10  is H, alkyl, cycloalkyl, aryl, heteraryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and  
     R 11  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR 12 , CONR 7 R 8 , S(O) q R 12  or S(O) q NR 7 R 8 ;  
     or R 10  and R 11  and the nitrogen to which they are attatched together represent a heterocyclic ring;  
     R 12  is OR 9  or R 13 ;  
     R 13  is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl;  
     R 14  is H, alkyl, or cycloalkyl;  
     R 15  is H, alkyl, cycloalkyl, arylalkyl or heteroarylalkyl;  
     R 16  is H or alkyl,  
     A is aryl or heteroaryl, provided that when A is phenyl, R 3  is H,  
     W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or haterocycloalkyl,  
     each k and m is independently 0, 1, 2 or 3;  
     n is 0 or 1; and  
     p is 0, 1 or 2;  
     or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof

FIELD OF THE INVENTION

[0001] This invention relates to hydroxamic and carboxylic acidderivatives, and to their use in medicine.

BACKGROUND OF THE INVENTION

[0002] Metalloproteinases, including matrix metalloproteinase (MMP),collagenase, gelatinase and TNFα convertase (TACE), and their modes ofaction, and also inhibitors thereof and their clinical effects, aredescribed in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, thecontents of which are incorporated herein by reference. MNP inhibitorsmay also be useful in the inhibition of other mammalianmetalloproteinases such as the ADAM or ADAM-TS families.

[0003] Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenase, stromelysin and gelatinase, have been shown to inhibit therelease of TNFα both in vitro and in vivo. See Gearing et al(1994),Nature 370:555-557; McGeehan etal (1994), Nature 370:558-561;GB-A-2268934; and WO-A-93/20047. All ofthese reported inhibitors containa hydroxamic acid zinc-binding group, as do the imidazole-substitutedcompounds disclosed in WO-A-95/23790. Other compounds that inhibit MMPand/or TNF(X are described in WO-A-95/13289, WO-A-96/11209,WO-A-96/035687, WO-A-96/03571 1, WO-A-96/035712 and WO-A-96/035714.

SUMMARY OF THE INVENTION

[0004] The invention encompasses novel compounds of formula (I) whichare inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, andwhich are usefuil for the treatment of diseases mediated by thoseenzymes and/or TNFα-mediated diseases, including degenerative diseasesand certain cancers.

[0005] Novel compounds according to a first aspect of the invention arerepresented by formula (I):

[0006] wherein

[0007] R¹ is OH or NHOH;

[0008] R² is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo orheterocycloalkyl (any of which may be optionally substituted with one ormore substituents selected from R⁶, W and WR6); and

[0009] R³ is H or alkyl;

[0010] or R², R³ and the carbon atom to which they are attached togetherrepresent a carbocyclic or heterocyclic ring (either of which may besubstituted with one or more substituents selected from R⁶, W and WR⁶);

[0011] R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R⁴, COR¹⁰, S(O)_(q)R¹⁰ where qis 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituents may beattached to the same carbon atom to form C(R⁴)₂, where each R⁴ may bethe same or different, and CC⁴)₂ may represent C═O;

[0012] R⁵ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹,COR¹⁰, S(O)_(q)R¹⁰, CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰OR¹¹ orCN, or two adjacent R⁵ substituents may be combined to form aheterocyclic ring;

[0013] R⁶ is OR⁹, COR¹⁰, CO₂R¹⁵, CONR⁷R, NRLOR^(1,) S(O)R¹⁰,S(O)_(q)NR⁷R⁸, ═O, ═NOR¹⁰, succinimido or the group

[0014] R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylallyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R¹ and the nitrogen towhich they are attached together represent a heterocyclic ring;

[0015] R⁹ is H, alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl,heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl orcycloalkylalkyl;

[0016] R¹⁰ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and

[0017] R¹¹ is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹²,CONR⁷R⁸, S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸;

[0018] or R¹⁰ and R¹¹ and the nitrogen to which they are attachedtogether represent a heterocyclic ring;

[0019] R¹² is OR⁹ or R¹³;

[0020] R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl;

[0021] R¹⁴ is H, alkyl or cycloalkyl;

[0022] R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;

[0023] R¹⁶ is H or alkyl;

[0024] A is aryl or heteroaryl, provided that when A is phenyl, R³ is H;

[0025] W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;

[0026] each k and m is independently 0, 1, 2 or 3;

[0027] n is 0, 1 or 2; and

[0028] p is 0, 1 or 2;

[0029] or a salt, solvate, hydrate, N-oxide, protected amino, protectedcarboxy or protected hydroxamic acid derivative thereof

DESCRIPTION OF THE INVENTION

[0030] It will be appreciated that the compounds according to theinvention can contain one or more asymmetrically substituted carbonatoms. The presence of one or more of these asymmetric centres in acompound offormula (I) can give rise to stereoisomers, and in each casethe invention is to be understood to extend to all such stereoisomers,including enantiomers and diastereomers, and mixtures including racemicmixtures thereof

[0031] It will further be appreciated that the compounds according tothe invention may contain an oxime. This oxime can give rise togeometrical isomers, and in each case the invention is to be understoodto extend to all such isomers and mixtures thereof

[0032] As used in this specification, alone or in combination, the term“alkyl” refers to straight or branched chain alkyl moiety having fromone to six carbon atoms, including for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

[0033] The term “alkenyl” refers to a straight or branched chain alkylmoiety having two to six carbon atoms and having in addition one doublebond, of either E or Z stereochemistry where applicable. The termalkenyl includes for example, vinyl, 1-propenyl, 1- and 2- butenyl, 2-methyl-2-propenyl and the like.

[0034] The term “alkynyl” refers to a straight or branched chain alkylmoiety having two to six carbon atoms and having in addition one triplebond. The term altynyl includes for example, ethynyl, 1-propynyl, 1- and2- butynyl, 1- methyl-2-butynyl and the like.

[0035] Cycloalkyl or carbocyclic ring refers to a non-aromatic cyclic ormulticyclic, saturated or partially saturated ring system having fromthree to ten carbon atoms which may be optionally benzofused at anyavailable position. Thus cycloalkyl includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,tetrahydronaphthyl, bicyclo[2.2. 1]heptanyl, bicyclo[2.2. I]heptenyl,cyclopentenyl, indanyl and the like.

[0036] Heterocyclo or heterocyclic ring refers to a 3 to 10 memberedsaturated or partially saturated monocyclic or saturated or partiallysaturated multicyclic hydrocarbon ring system in which one or more ofthe atoms in the ring system is an element other than carbon, chosenfrom amongst nitrogen, oxygen or sulphur (or oxidised versions thereof,such as N-oxide, sulphoxide, sulphone). Examples include azetidinyl,pyrrolidinyl, 1 5 tetrahydrofuryl, piperidinyl, quinuclidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl,N-alkyl-piperazinyl, homopiperazinyl, oxazolidinyl, imidazolidinyl,thiazolidinyl, pyrazolidinyl, benzodioxole, [2,3-dihydro]benzofuryl,[3,4-dihydro]benzopyranyl, 1,2,3,4 tetrahydroquinolinyl, 1,2,3,4tetrahydroisoquinolinyl, 8-oxabicyclo[3.2.1]octane, indolinyl,isoindolinyl, and the like.

[0037] Aryl indicates carbocyclic radicals containing 6 to 10 carbonatoms and containing either a single ring or two condensed rings. Thusaryl includes, for example, phenyl and naphthyl.

[0038] Heteroaryl refers to a 5 to 10 membered aromatic monocyclic ormulticyclic hydrocarbon ring system in which one or more of the atoms inthe ring system is an element other than carbon, chosen from amongstnitrogen, oxygen or sulphur (or oxidised versions thereof, such asN-oxide). In general, the heteroaryl groups may be for examplemonocyclic or bicyclic fused ring heteroaryl groups. Monocyclicheteroaryl groups include, for example, five- or six-membered heteroarylgroups containing one, two, three or four heteroatoms selected fromoxygen, sulphur or nitrogen atoms. Bicyclic heteroaryl groups includefor example eight- to ten-membered fused-ring heteroaryl groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms.

[0039] The term heteroaryl includes, for example, pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl,pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl,benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl,benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, phthalazinyl,tetrazolyl and the like.

[0040] Arylalkyl includes an aryl-alkyl- group wherein the aryl andalkyl are as described herein. Heteroarylalkyl includes aheteroaryl-alkyl- group, cycloalkylalkyl includes a cycloalkyl-alkyl-group and heterocycloalkyl includes a heterocyclo-alkyl- group, whereinall groups are as defined above.

[0041] The term “halogen” includes fluorine, chlorine, bromine oriodine.

[0042] The term “benzofused” means the addition of a benzene ringsharing a common bond with the defined ring system.

[0043] The term “optionally substituted” means optionally substituted byone or more of the groups specified, at any available position orpositions.

[0044] The terms “protected amino”, “protected carboxy” and “protectedhydroxamic acid” mean amino, carboxy and hydroxamic acid groups whichcan be protected in a manner familiar to those skilled in the art. Forexample, an amino group can be protected by a benzyloxycarbonyl,tert-butoxycarbonyl, acetyl or like group, or may be in the form of aphthalimido or like group. A carboxyl group can be protected in the formof a readily-cleavable ester such as the methyl, ethyl, benzyl ortert-butyl ester. A hydroxamic acid may be protected as either N orO-substituted derivatives, such as O-benzyl orO-tert-butyldimethylsilyl.

[0045] Salts of compounds of formula (I) or formula (II) includepharmaceutically-acceptable salts, for example acid addition saltsderived from inorganic or organic acids, such as hydrochlorides,hydrobromides, p-toluenesulphonates, phosphates, sulphates,perchlorates, acetates, trifluoroacetates, propionates, citrates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

[0046] Salts may also be formed with bases. Such salts include saltsderived from inorganic or organic bases, for example alkali metal saltssuch as magnesium or calcium salts, and organic amine salts such asmorpholine, piperidine, dimethylamine or diethylarnine salts.

[0047] When the “protected carboxy” group in compounds ofthe inventionis an esterified carboxyl group, it may be a metabolically-labile esterof formula CO₂R where R may be an ethyl, benzyl, phenethyl,phenylpropyl, (x or O-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl orpivaloylmethyl group.

[0048] Preferred compounds of the invention are those wherein any one ormore of the following may apply:

[0049] One group of compounds of the invention has the formula (I) inwhich R¹ is NHOH.

[0050] In one preferred group of compounds of formula (I) R² is inparticular isopropyl or isobutyl, especially isopropyl.

[0051] Another preferred group of compounds of formula (I) is where R²is a substituted alkyl group, especially substituted methyl, ethyl orpropyl. R² in compounds of this type is preferably substituted by R⁶,where R⁶ is especially CO₂R¹⁵, in particular CO₂H, CONR⁷R⁸, NR¹⁰OR¹¹,succinimido or the group

[0052] In compounds of this type CONR⁷R⁸ is in particular CON(H)₂,CON(H)alkyl, CON(alkyl)₂ or R⁷ and R¹ are attached together to form aheterocyclic ring. NR¹⁰R¹¹ in compounds ofthis type is especiallyN(H)COR¹² or N(alkyl)COR¹², particularly preferred is where R¹² isalkyl. Each R¹⁶ in compounds of the invention is in particular methyl.

[0053] A further preferred group of compounds ofthe invention has theformula (I) where R² is an optionally substituted cycloalkyl orheterocyclo group, especially an optionally substituted heterocyclogroup. In compounds of this type R² is in particular azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl ortetrahydropyranyl, especially optionally substituted piperidinyl. Whensubstituted compounds of this type may in particular be substituted byR⁶, especially where R⁶ is CO₂R¹⁵. R¹⁵ may in particular be arylalkyl orheteroarylalkyl, preferably arylalkyl, especially benzyl.

[0054] R³ in compounds of the invention may in particular be a hydrogenatom.

[0055] One group of compounds of the invention has the formula (I) inwhich R², R³ and the carbon atom to which they are attached togetherrepresent an optionally substituted carbocylic or heterocyclic ring.Especially preferred compounds in this group are those where CR²R³ is acycloalkyl or a heterocyclic ring, in particular, C₃₋₇ cycloalkylgroups, especially, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexylgroups, and C₃₋₇ heterocyclo groups, especially, azetidinyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl andpiperazinyl. In compounds of this type CR²R³ is in particularcyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl.

[0056] Especially preferred is where p=1 and n=1.

[0057] In compounds of the invention k is preferably 0.

[0058] R⁵, when present may in particular be C₃₋₇ cycloaLkyl, aryl,monocyclic heteroaryl, C₃₋₇ heterocyclo, CF₃, OR⁹, CONR⁷R⁸, F, Cl, Br, Ior CN. Especially preferred is where Rs is cyclobutyl, cyclopentyl,cyclohexyl, phenyl, CF₃, OCH₃, OCF₃, OCHF₂, OCH₂F, CONH₂, CONHCH₃,CON(CH₃)₂, CN, F, Cl, Br or I. In compounds where R⁵ is present m ispreferably 1 or 2.

[0059] One particular group of compounds of interest is represented bythe formula (Ia):

[0060] wherein R¹, R², R⁴, R⁵, k and m, n and p are as previouslydescribed. In compounds of formula (Ia) R³ is a hydrogen atom.

[0061] Another group of compounds has the formula (I) wherein A is inparticular pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl or 1,2,3-triazinyl,especially thiazolyl.

[0062] Particularly preferred compounds of the invention are:

[0063] 1-[2-(3,4-Dihydro-H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoyl-ethyl]-piperidine-1-carboxylicacid benzyl ester;

[0064] 2-(6-Cyclohexyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide;

[0065]N-Hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide;

[0066]2-(6,7-Dimethoxy-3,4-dihydro-IH-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide;

[0067]N-Hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyramride;

[0068] and the salts, solvates, hydrates, N-oxides, protected amino,protected carboxy and protected hydroxamic acid derivatives thereof.

[0069] Compounds of the general formula (I) may be prepared by anysuitable method known in the art and/or by the following processes.

[0070] It will be appreciated that, where a particular stereoisomer offormula (1) is required, the synthetic processes described herein may beused with the appropriate homochiral starting material and/or isomersmaybe resolved from mixtures using conventional separation techniques(e.g. HPLC).

[0071] The compounds according to the invention may be prepared by thefollowing process. In the description and formulae below, the variousgroups R and other variables are as defined above, except whereotherwise indicated. It will be appreciated that functional groups, suchas amino, hydroxyl or carboxyl groups, present in the various compoundsdescribed below, and which it is desired to retain, may need to be inprotected form before any reaction is initiated. In such instances,removal of the protecting group may be the final step in a particularreaction. Suitable protecting groups for such functionality will beapparent to those skilled in the art. For specific details see Greene etal, “Protective Groups in Organic Synthesis”, Wiley Interscience (1999).

[0072] Thus, for example, compounds of the invention may be prepared bythe following general route:

[0073] Compounds of formula (IV), where W is for example an alkoxygroup, such as methoxy, ethoxy or tert-butoxy or a chiral auxiliary, forexample, 4-(R)-benzyloxazolidin-2-one, may be prepared by methods wellknown in the literature, for example, by reaction of a sulfonyl chloride(II) with an amine (III) in the presence of an amine base, such astriethylamine in a halogenated solvent, such as dichloromethane at roomtemperature.

[0074] Compounds of general formula (II) are either known or may be madeby one skilled in the art using methods known in the literature, see forexample WO-A-99/24399, or as described in the examples herein after.Compounds of general formula (III) are available commercially or they bemade using methods known in the literature or by any method known tothose skilled in the art. For example, an amine of general formula (III)may be prepared by selective hydrogenation of a heteroaryl group, suchas isoquinoline using for example a platinum catalyst under acidicconditions. Appropriate conditions may be platinum (IV) oxide in thepresence of concentrated hydrochloric acid in ethanol under a pressureof 690 kPa. Alternatively, an amine of formula (III) where A is aheteroaryl group such as thiazolyl or oxazolyl may be prepared byformation of such a heteroaryl group on a suitably functionalised aminering such as N-tert-butoxycarbonyl-protected piperidin-4-one using wellknown methods. For example, the piperidinone (V) may be a-halogenatedusing standard conditions, such as reaction of the ketone withtrimethylsilyl chloride and an amine base such as triethylamine inN,N-dimnethylformamide at 70° C., followed by c-halogenation using, forexample, N,N-bromosuccinimide in a suitable solvent such asacetonitrile. The α-bromoketone (VI) may then be reacted with a suitableamide or thioamide, such as thiobenzamide in conditions such asN,N-dimethylformamide at 80° C., to form the desired heteroaryl ring, asillustrated in the scheme below:

[0075] Carboxylic acids of general formula (I) may be prepared bydeprotection of a suitably protected carboxylic acid of formula (IV).For example, where W is an alkoxy group, such as ethoxy, a base such asaqueous lithium hydroxide may be used, alternatively trifluoroaceticacid may be used when W is a tert-butyl group or in the case of a chiralauxiliary such as 4-(R)-benzyl-oxazolidin-2-one, lithiumhydroxide/hydrogen peroxide may be used. Appropriate solvent andtemperature conditions such as those described in the examples hereinafter may be used.

[0076] Compounds of formula (I) may also be prepared by interconversionof other compounds of formula (I). Thus, for example, hydroxamic acidsof general formula (1) may be prepared using conditions well known inthe literature. For example, treatment of acids of formula (I) withoxalyl chloride in an inert solvent (such as dichloromethane) gives anintermediate acid chloride, which may or may not be isolated, but whichin turn is reacted with hydroxylamine at a suitable temperature such asroom temperature to give the desired hydroxamic acids (I). Alternativelyan acid of formula (I) maybe activated in situ using for example adiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, advantageously in the presence of a catalyst such as aN-hydroxy compound, e.g. N-hydroxybenzotriazole using suitableconditions, e.g. in N,N-dimethylformamide at -15° C., prior to thesubsequent addition of a suitably protected hydroxylamine such astert-butyldimethyl silyl hydroxylamine and warming to ambienttemperature. The protecting group maybe removed using appropriateconditions, such as water or tetrabutylanunonium fluoride and aceticacid in tetrahydrofuran at 0C, to yield the desired hydroxamic acids offormula (I).

[0077] Similarly, intermediates of any appropriate formula may beprepared by the interconversion of other compounds of the same formula.

[0078] Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

[0079] The compounds according to the invention exhibit in vitroinhibiting activities with respect to the stromelysin, collagenase,gelatinase, ADAM or ADAM-TS enzymes. 20 Compounds according to theinvention may also exhibit in vitro inhibition of membrane-sheddingevents known to be mediated by metalloproteinases, for example, α-APP,ACE, TGF-α, TNF-α, Fas ligand, selectins, TNFR-I, TNFR-II, CD30, Il-6R,CD43, CD44, CD16-I, CD16-II, Folate receptor, CD23, or IL-1RII.

[0080] The activity and selectivity of the compounds may be determinedby use of the 25 appropriate enzyme inhibition test, for example asdescribed in Examples A-M of WO-A-98/05635, bythe assay for theinhibition of CD23 shedding described in WO-A-99/24399, or by the assayof TNF RI shedding described in WO-A-00/56704.

[0081] This invention also relates to a method of treatment for patients(including man and/or mammalian animals raised in the dairy, meat or furindustries or as pets) suffering from disorders or diseases which can beattributed to metalloproteinases.

[0082] Accordingly, the compounds of formula (I) can be used among otherthings in the treatment of osteoarthritis and rheumatoid arthritis, andin diseases and indications resulting from the over-expression of thesematrix metalloproteinases such as found in certain metastatic tumourcell lines.

[0083] As mentioned above, compounds of formula (I) are useful in humanor veterinary medicine since they are active as inhibitors of TNF andMMPs. Accordingly in another aspect, this invention concerns:

[0084] a method of management (by which is meant treatment orprophylaxis) of disease or conditions mediated by TNF, MMPs, ADAM orADAM-TS enzymes, in mammals, in particular in humans, which methodcomprises administering to the mammal an effective, amount of a compoundofformula (I) above, or a pharmaceutically acceptable salt thereof; and

[0085] a compound of formula (I) for use in human or veterinarymedicine, particularly in the management (by which is meant treatment orprophylaxis) of diseases or conditions mediated by TNF, MMPs, ADAM orADAM-TS enzymes; and

[0086] the use of a compound of formula (I) in the preparation of anagent for the management (by which is meant treatment or prophylaxis) ofdiseases or conditions mediated by TNF, MMPs, ADAM or ADAM-TS enzymes.

[0087] The disease or conditions referred to above include inflammatorydiseases, autoimmune diseases, cancer, cardiovascular diseases anddiseases involving tissue breakdown. Appropriate diseases includerheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration,Alzheimer's disease, stroke, vasculitis, Crohn's disease, ulcerativecolitis, multiple sclerosis, periodontitis, gingivitis and thoseinvolving tissue breakdown such as bone resorption, haemorrhage,coagulation, acute phase response, cachexia and anorexia, acuteinfections, bacterial infections, HIV infections, fever, shock states,graft versus host reactions, dermatological conditions, surgical woundhealing, psoriasis, atopic dermatitis, epidermolysis bullosa, tumourgrowth, angiogenesis and invasion by secondary metastases,ophthalmological disease, retinopathy, corneal ulceration, reperfusioninjury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis,eczema, anaphylaxis, restenosis, congestive heart failure,endometriosis, atherosclerosis, endosclerosis, aspirin-independentantα-thrombosis, systemic lupus erythematosus and solid organtransplant.

[0088] Compounds of formula (I) may also be useful in the treatment ofpelvic inflammatory disease (PID), age-related macular degeneration andcancer-induced bone resorption. Further, they can be used in thetreatment of lung diseases, e.g. selected from cystic fibrosis, adultrespiratory distress syndrome -(ARDS), emphysema, bronchitisobliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis(PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).

[0089] Compounds of the invention are particularly of use in thetreatment of inflammatory diseases, autoimmune diseases and cancer.Thus, for example, the compounds may be used in the treatment (includingprophylaxis) of graft versus host reactions, psoriasis, atopicdermatitis, rhinitis, eczema, systemic lupus erythematosus, solidorgantransplant, cystic fibrosis, rheumatoid arthritis, osteoarthritis,osteoporosis, Crohn's Disease, ulcerative colitis, multiple sclerosis,periodontitis, bone resorption, bacterial infections, epidermolysisbullosa, tumour growth, angiogenesis, ophthalmological disease,retinopathy, asthma, emphysema, bronchitis, and chronic obstructivepulmonary disease (COPD).

[0090] For the treatment of all diseases and disorders previouslyindicated, the compounds of formula (I) may be administered orally,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing non-toxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenteral as used herein includessubcutaneous injections, intravenous, intramuscular, intrasternalinjection orinfusiontechniques. Ocular injection, such as intravitreal,subtenons, subconjunctival, periocular and retrobulbar may also be used,as well as intraocular slow release devices and implants. In addition tothe treatment ofwarm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats etc, the compounds of the invention are effective inthe treatment of humans.

[0091] The pharmaceutical composition containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from sweetening agents, flavouring agents, colouring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture oftablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example corn starch, or alginic acid; bindingagents, for example starch, gelatin or acacia, and lubricating agents,for example magnesium stearate, stearic acid or talc. The tablets may beuncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. They may also be coated by the techniques described in theU.S. Pat. No. 4256108, U.S. Pat. No. 4166452 and U.S. Pat. No. 4265874,to form osmotic therapeutic tablets for controlled release.

[0092] Formulations for oral use may also be presented as hard gelatincapsules where in the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0093] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one ormore colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

[0094] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an antα-oxidant such as ascorbic acid.

[0095] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified, for example sweetening,flavouring and colouring agents may also be present.

[0096] The pharmaceutical compositions ofthe invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

[0097] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be ina sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0098] A compound ofthe invention may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0099] For topical use, creams, ointments, jellies, solutions orsuspensions, etc, containing a compound of the invention are employed.For the purposes ofthis specification, topical application includesmouthwashes and gargles.

[0100] For topical ocular administration, pharmaceutically acceptablesolutions, suspensions or gels containing the compounds of formula (I)may be used. Solutions and suspensions may also be adapted forintra-vitreal or intra-cameral use.

[0101] Dosage levels of the order of from about 0.05 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 2.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg ofthe compound per kilogramof body weight per day (about 0.5 mg to about 3.5 g per patient perday).

[0102] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay vary from about 5 to about 95% of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofactive ingredient.

[0103] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

[0104] The following Examples illustrate the invention.

[0105] The following abbreviations are used: Boc-tert-butoxy carbonyl;DCM-dichloromethane DMF-N,N-dimethylformamide EtOAc-ethyl acetateMeOH-methanol NBS-N-bromosuccinimide TFA-trifluoroacetic acid

[0106] Intermediate 1 6-Cyclohexyl-1,2,3,4tetrahydro-isoquinoline

[0107] Platinum (IV) oxide (30mg), then 12M hydrochloric acid (1.5ml)was added to a solution of 6-phenyl-isoquinoline (1 .52g) in ethanol(30ml). The mixture was transferred to a Parr high pressure apparatusand charged with hydrogen to a pressure of 50 psi. The reaction wasstirred at room temperature for 3 h then recharged with hydrogen to 100psi and left to stir for 16 h. The mixture was then filtered, freshplatinum catalyst and 12M hydrochloric acid added, and the Parr highpressure apparatus charged to 75 psi. The reaction was left to stir atroom temperature for 16 h, after which a white crystalline solid wasobserved in the reaction mixture. Water was added to dissolve this solidand the mixture filtered through celite, washing with 1:1 water-methanol(3×30 ml). The methanol was removed under reduced pressure then theaqueous basified with concentrated sodium hydroxide solution andextracted with 2:1 diethyl ether-ethyl acetate (3×50 ml). The combinedextracts were washed with water (2×20 ml), saturated sodium bicarbonate(20 ml) and brine (20 ml) then dried (Na₂SO₄), filtered and evaporatedunder reduced pressure. The residue was purified by chromatography(SiO₂, 93:6:1 dichloromethane-methanol-ammonia, then a second columnwith 94:5:1 dichloromethane-methanol-ammonia) to give the title compound(190 mg) as a mixture containing approximately 20% of a slightly higherrunning product.

[0108] R_(f) 0.27 (94:5:1 dichloromethane-methanol-ammonia)

[0109] Intermediate 2 4 Benzenesulfonyloxy-piperidine-1-carboxylic acidbenzyl ester

[0110] Triethylamine (17 ml) was added dropwise to a solution of benzyl4-hydroxy-1-piperidinecarboxylate (28.83 g) in dichloromethane (lOOml)at 0° C. and stirred for 15 minutes. Benzenesulfonyl chloride (14 ml)was added and the reaction allowed to stir at room temperature for 48 h.The mixture was washed with water (50 ml), saturated sodium bicarbonatesolution (50 ml), water (50 ml) and brine (50 ml) then dried (Na₂SO₄),filtered and evaporated under reduced pressure. The residue was purifiedby chromatography (SiO₂, 20% ethyl acetate in hexane to 30% ethylacetate in hexane) to give the title compound (31.88 g, 77%) as a whitecrystalline solid. R_(f) 0.62 (5% methanol in dichloromethane)

[0111] Intermediate 3 2-(1-Benzyloxycarbonyl-piperidin-4 yl)-malonicacid

[0112] Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under anitrogen atmosphere at room temperature. A solution of diethyl malonate(56.4 ml) in ethanol (50 ml) was added dropwise, followed by a solutionof 4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88g) in ethanol (50 ml), also added dropwise. The mixture was heated toreflux for 16 h then the solvent was removed under reduced pressure. Theresidue was partitioned between water (100 ml) and diethyl ether (100ml) and the aqueous washed with further diethyl ether (60 ml). Thecombined organics were washed with 10% citric acid solution (50 ml),water (50 ml) and brine (50 ml). After drying (Na₂SO₄) and filtering thesolvent was removed under reduced pressure to leave a yellow liquid.Half of this crude diester was taken and dissolved in methanol (150 ml)and water (50 ml). Lithium hydroxide monohydrate (18.14 g) was addedslowly and the reaction left to stir at room temperature for 16 h thenthe methanol was removed under reduced pressure. The aqueous was washedwith diethyl ether (3×40 ml), acidified to pH=3 with citric acid andextracted with ethyl acetate (2×40 ml). The combined organics werewashed with water (2×40 ml) and brine (40 ml), dried (Na₂SO₄), filteredand evaporated under reduced pressure to give the title compound (8.29g, 56%) as a white crystalline solid.

[0113] R_(f) 0.47 (5% methanol in dichloromethane)

[0114] Intermediate 4 4 (1-Carboxy-vinyl)-piperidine-1-carboxylic acidbenzyl ester

[0115] 2-(1-Benzyloxycarbonyl-piperidin-4-yl)-malonic acid (18.06 g) wasdissolved in tetrahydrofuran (140 ml) and morpholine (4.95 ml) followedby acetic acid (6.43 ml) was added, forming a white precipitate.Formaldehyde (4.56 g) was added, causing the precipitate to disappear,and the mixture heated to reflux for 4 h. The solvent was evaporated,diethyl ether (50 ml) added and the mixture extracted with water (3×60ml). The aqueous was acidified to pH═3 with citric acid and extractedwith diethyl ether (3×30 ml). The combined organic extracts were washedwith water (40 ml) and brine (40 ml), dried (Na₂SO₄), filtered and thesolvent removed under reduced pressure to give the title compound (16.65g) as a mixture containing approximately 10% of the acid startingmaterial.

[0116] R_(f) 0.5 (5% methanol in dichloromethane)

[0117] Intermediate 5 4-(2-Acetylsulfanyl-1-carboxy-ethyl)-piperidine-1carboxylic acid benzyl ester

[0118] 4-(1-Carboxy-vinyl)-piperidine-1-carboxylic acid benzyl ester(15.6 g) was dissolved in thioacetic acid (lSml) and heated to refluxfor 3 h. The thioacetic acid was evaporated under reduced pressure andazeotroped with 1:1 hexane-dichloromethane (4×30 ml) to give the titlecompound (20.32 g, 95%) as an orange oil. R_(f) 0.28 (40% ethyl acetatein hexane)

[0119] Intermediate 6 4(2-Acetylsulfanyl-1-tert-butoxycarbonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester

[0120] Sulfuric acid (1. 1Sml) was added slowly to a solution of4-(2-acetylsulfanyl-1-carboxy-ethyl)-piperidine-1-carboxylic acid benzylester (20.32 g) in dichloromethane (60 ml). The mixture was cooled in anacetone/dry ice bath and cooled isobutylene (60 ml)added. The mixturewas transferred to a Parr high pressure apparatus and left to stirovernight then washed with water (30 ml), saturated sodium bicarbonatesolution (30 ml) and brine (30 ml). After drying (Na₂SO₄) and filteringthe solvent was removed under reduced pressure and the residue purifiedby column chromatography (SiO₂, 20% ethyl acetate in hexane) to give thetitle compound (11.22 g, 60%) as an orange oil.

[0121] R_(f) 0.25 (20% ethyl acetate in hexane)

[0122] Intermediate 7 4 (1-tert-Butoxycarbonyl-2hlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester

[0123] A solution of4-(2-acetylsulfanyl-1-tert-butoxycarbonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester (1.01 g) in dichloromethane (25 ml) and water (25 ml)was cooled in ice. Chlorine gas (500 mg) was bubbled through thesolution over 10 minutes then the mixture was flushed with nitrogen gas.The mixture was washed with water (25 ml) and brine (25 ml), then dried(Na₂SO₄), filtered and the solvent removed under reduced pressure togive the title compound (920 mg, 86%) as a colourless oil.

[0124] R_(f) 0.48 (30% ethyl acetate in hexane)

[0125] Intermediate 84-[1-tert-Butoxycarbonyl-2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-ethyl]-piperidine-1-carboxylicacid benzyl ester

[0126] 1,2,3,4- Tetrahydroisoquinoline (0. 17 ml) was dissolved indichloromethane (40 ml) at room temperature under nitrogen.Triethylamine (0.19 ml) was added, followed by4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylicacid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml).The reaction was left to stir for 64 h then diluted with dichloromethane(60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml).The organic layer was then dried (MgSO₄), filtered and the solventremoved under reduced pressure to give the title compound (506 mg, 83%)as a yellow oil.

[0127] R_(f) 0.44 (50% ethyl acetate in heptane)

[0128] The following compounds were prepared as above.

[0129] Intermediate 9 3-Methyl-2- (6-phenyl-3-4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyric acid tert-butyl ester

[0130] From 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butylester (293 mg) and 6-phenyl-1,2,3,4-tetrahydro-isoquinoline (206 mg) togive, after chromatography (SiO₂, 25% diethyl ether in hexane), thetitle compound (340 mg, 78%) as a white solid.

[0131] R_(f) 0.24 (25% diethyl ether in hexane)

[0132] Intermediate 102-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid tert-butyl ester

[0133] From 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butylester (²63 mg) and 6-cyclohexyl-1,2,3,4-tetrahydro-isoquinoline (190 mg)to give, after chromatography (SiO₂, 25% diethyl ether in hexane), thetitle compound (230 mg, 58%) as a colourless gum.

[0134] R_(f) 0.36 (25% diethyl ether in hexane)

[0135] Intermediate 11 1-tert-Butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine

[0136] Trimethylsilyl chloride (25 ml) and triethylamine (50 ml) wereadded to a stirred solution of N-Boc piperidinone (30 g) in DMF (40 ml)and the mixture was heated at 70 ° C. for 16 h. The solution was cooledto room temperature and diluted with hexanes (300 ml), the solution waswashed with sodium bicarbonate solution (3 x 100 ml), dried (MgSO₄) andevaporated to give a colourless oil. The product was purified on silicaeluting with 10% ethyl acetate/hexanes to give the title compound ascolourless oil (25 g, 62%).

[0137] R_(f) 0.7 (20% EtOAc/hexanes)

[0138] Intermediate 12 1-tert-Butoxycarbonyl-3-bromopiperidin-4-one

[0139] NBS (1.4 g) was added to a solution of1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine(2 g) in acetonitrile and the mixture was stirred at room temperaturefor 30 minutes. The solution was diluted with ethyl acetate(50 ml) andwashed with water (50 ml), sodium bicarbonate solution (50 ml) and brine(50 ml), dried (MgSO₄) and evaporated to give the title compound as acolourless solid (1.8 g).

[0140] R_(f) 0.40 (20% EtOAc/hexanes)

[0141] Intermediate 132-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4c]pyridine

[0142] A solution of 1-tert-butoxycarbonyl-3-bromopiperidin-4-one (8 g)and thiobenzamide (3.4 g) in DMF was heated at 70 ° C. for 16 h, thencooled to room temperature. The solvent was evaporated in vacuo and theresidue dissolved in water (100 ml) and washed with ether (100 ml), thenbasified with sodium hydroxide and extracted into ethyl acetate (3×100ml). The solvent was dried (MgSO₄) and evaporated to give the titlecompound as cream solid (2.81 g, 53% based on thiobenzamide used). MS217 (M+1)

EXAMPLE 1 3-Methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyric acid

[0143] Trifluoroacetic acid (5 ml) was added to a solution of3-methyl-2-(6-phenyl-3-4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid tert-butyl ester (0.33 g) in dichloromethane (20 ml). The reactionwas stirred at room temperature for 4 h then evaporated under reducedpressure. Diethyl ether (10 ml) was added to the residue then extractedwith 1M sodium hydroxide solution. The aqueous was extracted withdiethyl ether (10 ml), acidified with citric acid to pH═3 then extractedwith ethyl acetate (3×10 ml). The combined ethyl acetate extracts werewashed with water (2×10 ml) and brine (10 ml), dried (Na₂SO₄), filteredand evaporated under reduced pressure to give the title compound (250mg, 87%) as a white solid.

[0144] R_(f) 0.26 (50% diethyl ether in hexane plus acetic acid) MS 388(M+1), 386 (M−1)

[0145] The following compound was prepared as above.

EXAMPLE 22-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid

[0146] From 2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyric acid tert-butyl ester(230 mg) to give the title compound (164 mg, 82%) as a white solid.

[0147] R_(f) 0.27 (50% diethyl ether in hexane plus acetic acid) MS 394(M+1), 392 (M−1)

EXAMPLE 3 2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2sulfonylmethyl)-3-methyl-butyric acid

[0148] 2-Chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester(l.Oml of a 1M solution in dichloromethane) was added to a solution of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (230 mg) andtriethylamine (0.31 ml) in dichloromethane (10 ml) and the mixturestirred at room temperature for 16 h. Trifluoroacetic acid was added (5ml) and the reaction left to stir for 2 h then diluted with hexane (10ml) and evaporated under reduced pressure. The residue was azeotropedwith 1:1 dichloromethane-hexane (2×10 ml), dissolved in 1M sodiumhydroxide and washed with diethyl ether (2×10 ml); The aqueous wasacidified to pH═4 with citric acid and extracted with ethyl acetate (2xl5 ml). The combined extracts were washed with water (lOmil) and brine(10 ml), dried (Na2SO₄), filtered and evaporated under reduced pressureto give the title compound (93 mg, 25%).

[0149] R_(f) 0.43 (5% methanol in dichloromethane) MS (M+1) 372 and(M−1) 370

EXAMPLE 4 3-Methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyric acid

[0150] 2-Phenyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.11 g) wasadded to a solution of 2-chlorosulfonylmethyl-3-methyl-butyric acidtert-butyl ester (0.14 g) and triethylamine (0.3 ml) in DCM (20 ml) atroom temperature. The solution was stirred for 2 h, then TFA (5 ml) wasadded and the mixture stirred for 1 h. The mixture was evaporated invacuo and the residue partitioned between diethyl ether (10 ml) andsaturated sodium bicarbonate (30 ml). The aqueous layer was acidifiedwith citric acid to pH 5 and extracted with ethyl acetate (3×20 ml). Thesolvent was dried (MgSO₄) and evaporated to give the title compound aspale yellow solid (0.15 g).

[0151] R_(f) 0.32 (EtOAc)

EXAMPLE 5 1-[2-(3,4-Dihydro-1H-isoquinoline-2sulfonyl)-1-hydroxycarbamoyl-ethyl]-piperidine-1-carboxylic acid benzylester

[0152] Trifluoroacetic acid (5.0 ml) was added to a solution of4-[1-tert-butoxycarbonyl-2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)ethyl]-piperidine-1-carboxylicacid benzyl ester (506 mg) in dichloromethane (30 ml). The reaction wasstirred at room temperature for 3.5 h then the solvent and excesstrifluoroacetic acid evaporated under reduced pressure to give thecarboxylic acid as a yellow solid. This was dissolved in dichloromethane(30 ml) under a nitrogen atmosphere and oxalyl chloride (0. lml) added,followed by N,N-dimethylformamide (a few drops, catalytic). The reactionwas left to stir for 16 h then evaporated under reduced pressure to givethe acid chloride as a yellow solid. This was suspended intetrahydrafuran (10 ml) and 50% wt solution of aqueous hydroxylamine(0.30 ml) was added. The reaction was left to stir at room temperaturefor 20 minutes then the solvent was evaporated under reduced pressure.The residue was triturated with water (20 ml), the resulting solidfiltered off and washed with water (10 ml). Purification by reversephase preparative HPLC using a 25 cm×21.4 mm Phenomenex Luna C18 (2) (5u) column and a mobile phase of aqueous trifluoroacetic acid (0.05% v/v)and acetonitrile under gradient conditions from 20% to 70% acetonitrilegave the title compound (83 mg, 18%) as a pale yellow solid, >98% pureby HPLC analysis.

[0153] R_(f) 0.18 (5% methanol in dichloromethane) MS 500 (M−1)

EXAMPLE 62-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methyl-butyramide

[0154] 2-(6-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyric acid (143 mg) wasdissolved in dichloromethane (15 ml) under a nitrogen atmosphere andoxalyl chloride (0.15 ml) added, followed by a solution of 10%N,N-dimethylformamide in dichloromethane (7 drops). The reaction wasstirred at room temperature for 2 h then evaporated under reducedpressure and azeotroped with 1:1 dichworomethane-hexane (2×10 ml). Theresidue was dried under vacuum then suspended in tetrahydrofuran (15 ml)and treated with 50% wt solution of aqueous hydroxylamine (0.7 ml). Themixture was left to stir at room temperature for lh then evaporatedunder reduced pressure. The residue was triturated with water (20 ml)and the resulting solid filtered off, washed with water (10 ml) anddried under vacuum at 40 ° C. to give the title compound (120 mg, 82%).

[0155] R_(f) 0.32 (5% methanol in dichloromethane) MS 407 (M−1)

[0156] The following compounds were prepared as above.

EXAMPLE 7 N-flydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-IH-isoquinoline-2-sulfonylmethyl)-butyramide

[0157] From3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyricacid (230 mg), to give the title compound (220 mg, 93%).

[0158] R_(f) 0.28 (5% methanol in dichloromethane) MS 403 (M+1)

EXAMPLE 8 2 (6,7-Dimethoxy-3,4 dihydro-1H-isoquinoline-2sulfonylmethyl)-N-hydroxy-3-methyl-butyramide

[0159] From2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methyl-butyricacid (80 mg), to give the title compound (71 mg, 85%).

[0160] R_(f) 0.27 (5% methanol in dichloromethane) MS 387 (M+1)

EXAMPLE 9 N-Hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyramide

[0161] From 3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5 sulfonyl methyl)-butyric acid (0.15 g), togive the title compound as beige solid (85 mg).

[0162] R_(f) 0.33 (7% MeOH/DCM) MS 409 (M+1)

We claim:
 1. A compound of formula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸ ; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, ═O, ═NOR¹⁰,succinimido or the group

R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR¹², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸; or R¹⁰and R¹¹ and the nitrogen to whichthey are attached together represent a heterocyclic ring; R¹² is OR⁹ orR¹³; R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl or heteroaryl, provided that when A isphenyl, R³ is H; W is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;each k and m is independently 0, 1, 2 or 3; n is 0 or 1; and p is0, 1or2; or a salt, solvate, hydrate, N-oxide, protected amino, protectedcarboxy or protected hydroxamic acid derivative thereof.
 2. The compoundof claim 1, wherein R¹ is NHOH.
 3. The compound of claim 1, wherein R⁴is alkyl, cycloalkyl, OR⁹, CO₂R⁴, COR¹⁰, S(O)_(q)R¹⁰, CONR⁷R⁸, CN orS(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is not succinimido or the saidgroup; when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl or cycloalkyl; A is phenyl andR³ is H.
 4. The compound of claim 1, which is selected from3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)butyricacid, 2-(6-cyclohexyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,2-(6,7-dimethoxy-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,3-methyl-2-(2-phenyl-6,7-dihydro-4 H-thiazolo [5,4-c]pyridine-5-sulfonylmethyl)-butyric acid, 1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester, 2-(6-cyclohexyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide, 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide, andN-hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)butyramide.
 5. Apharmaceutical composition for use in therapy, comprising a compound offormula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF₃, OR⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R¹⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR⁹,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, ═0, ═NOR¹⁰,succinimido or the group

R⁷ and R^(8,) which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R⁸ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR², CONR⁷R⁸,S(O)_(q)R¹² or S(O)_(q)NR⁷R⁸; or R¹⁰ and R¹¹ and the nitrogen to whichthey are attached together represent a heterocyclic ring; R¹² is OR⁹ orR¹³; R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl or heteroaryl, provided that when A isphenyl, R³ is H; W is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;each k and m is independently 0, 1, 2 or 3; n is 0 or 1; and p is 0, 1or 2; or a salt, solvate, hydrate, N-oxide, protected amino, protectedcarboxy or protected hydroxamic acid derivative thereof; and apharmaceutically-acceptable diluent or carrier.
 6. The pharmaceuticalcomposition, according to claim 5, wherein R¹ is NHOH.
 7. Thepharmaceutical composition, according to claim 5, wherein R⁴ is alkyl,cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰, S(O)_(q)R¹⁰, CONR⁷R⁸, CN orS(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is not succinimido or the saidgroup; when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl or cycloalkyl; A is phenyl andR³ is H.
 8. The pharmaceutical composition, according to claim 5,wherein said compound is selected from 3-methyl-2-(6-phenyl-3,4-dihydro-1 H-isoquinoline-2-sulfonylmethyl)butyric acid,2-(6-cyclohexyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,2-(6,7-dimethoxy-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyric acid, 1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester, 2-(6-cyclohexyl-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide, 2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide, andN-hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)butyramide.
 9. A method forthe treatment of cancer; inflammation; an autoimmune, infectious orocular disease; or age-related macular degeneration; wherein said methodcomprises administering to a patient in need of such treatment aneffective amount of a compound of formula (I)

wherein R¹ is OH or NHOH; R² is H, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo or heterocycloalkyl (any of which may be optionallysubstituted with one or more substituents selected from R⁶, W and WR⁶);and R³ is H or alkyl; or R², R³ and the carbon atom to which they areattached together represent a carbocyclic or heterocyclic ring (eitherof which may be substituted with one or more substituents selected fromR⁶, W and WR⁶); R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R⁴, COR¹⁰, S(O)_(q)R¹⁰where q is 0, 1 or 2, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸; two R⁴ substituentsmay be attached to the same carbon atom to form C(R⁴)₂, where each R⁴may be the same or different, and C(R⁴)₂ may represent C═O; R⁵ is alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, CF3,0R⁹, COR¹⁰, S(O)_(q)R¹⁰,CO₂R⁴, CONR⁷R⁸, S(O)_(q)NR⁷R⁸, halogen, NR¹⁰R¹¹ or CN, or two adjacentR⁵ substituents may be combined to form a heterocyclic ring; R⁶ is OR⁹,COR¹⁰, CO₂R¹⁵, CONR⁷R⁸, NR¹⁰R¹¹, S(O)_(q)R¹⁰, S(O)_(q)NR⁷R⁸, ═0, ═NOR¹⁰,succinimido or the group

R⁷ and R⁸, which may be the same or different, are each H, alkyl,cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl,heterocycloalkyl or cycloalkylalkyl, or R⁷ and R¹ and the nitrogen towhich they are attached together represent a heterocyclic ring; R⁹ is H,alkyl, CF₃, CHF₂, CH₂F, cycloalkyl, aryl, heteroaryl, heterocyclo,arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁰ isH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and R¹¹ is H,alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR!², CONR⁷R⁸,S(O)_(q)R¹² or S(O)QNR⁷R⁸; or R¹⁰ and R¹¹ and the nitrogen to which theyare attached together represent a heterocyclic ring; R¹² is OR⁹ or R¹³;R¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; R¹⁴ is H, alkyl orcycloalkyl; R¹⁵ is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;R¹⁶ is H or alkyl; A is aryl or heteroaryl, provided that when A isphenyl, R³ is H; W is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;each k and m is independently 0, 1, 2 or 3; n is 0 or 1; and p is 0, 1or 2; or a salt, solvate, hydrate, N-oxide, protected amino, protectedcarboxy or protected hydroxamic acid derivative thereof. 10.The method,according to claim 9, wherein R¹ is NHOH.
 11. The method, according toclaim 9, wherein R⁴ is alkyl, cycloalkyl, OR⁹, CO₂R¹⁴, COR¹⁰,S(O)_(q)R¹⁰, CONR⁷R⁸, CN or S(O)_(q)NR⁷R⁸, or C(R⁴)₂ is C═O; R⁶ is notsuccinimido or the said group; when R⁶ is CO₂R¹⁵, R¹⁵ is H, alkyl orcycloalkyl; A is phenyl and R³ is H.
 12. The method, according to claim9, wherein said compound is selected from3-methyl-2-(6-phenyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)butyric acid, 2-( 6-cyclohexyl-3,4-dihydro-1 H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,2-(6,7-dimethoxy-3 ,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-3-methylbutyric acid,3-methyl-2-(2-phenyl-6,7-dihydro-4 H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)-butyric acid,1-[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-1-hydroxycarbamoylethyl]-piperidine-1-carboxylicacid benzyl ester, 2-(6-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramide,N-hydroxy-3-methyl-2-(6-phenyl-3,4-hydro-1H-isoquinoline-2-sulfonylmethyl)-butyramide,2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxy-3-methylbutyramideand N-hydroxy-3-methyl-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-sulfonylmethyl)butyramide.